IND-enabling preclinical development of a system for the multipurpose prevention of HIV and unintended pregnancy

支持 IND 的临床前开发系统，用于多用途预防艾滋病毒和意外怀孕

• 批准号: 9981612
• 负责人: Thomas J. Smith
• 金额: $ 100万
• 依托单位: AURITEC PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-08 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9981612
• 关键词: AIDS prevention; Animals; Anti-Retroviral Agents; Antiviral Agents; Chemistry; Clinical; Clinical Trials; Collaborations; Contraceptive Agents; Contraceptive methods; Data; Development; Devices; Dose; Drug Combinations; Drug Delivery Systems; Drug Kinetics; Engineering; Environment; FDA approved; Female of child bearing age; Formulation; Foundations; Fumarates; Goals; Grant; HIV; HIV Infections; HIV therapy; Half-Life; Hormones; Human; Infectious Pregnancy Complications; Integrase; Lead; Liquid substance; Macaca; Maintenance; Marketing; Mitochondria; Modeling; Nucleosides; Oryctolagus cuniculus; Pharmaceutical Preparations; Phase; Prevention; Principal Investigator; Process; Publishing; RNA-Directed DNA Polymerase; Recording of previous events; Regimen; Reporting; Research; Research Personnel; Safety; Sheep; Small Business Innovation Research Grant; System; Technology; Tenofovir; Testing; Therapeutic Index; Time; Toxic effect; United States National Institutes of Health; Vagina; Vaginal Ring; Woman; Work; base; cervicovaginal; commercialization; drug development; emtricitabine; experience; first-in-human; in vivo; inhibitor/antagonist; innovation; microbiome; novel; pre-clinical; pre-exposure prophylaxis; preclinical development; preclinical efficacy; product development; programs; response; scaffold; truvada; unintended pregnancy; uptake; vaginal microbiome

SUMMARY (changes are underlined) The broad, long-term goal of this research program is to develop an intravaginal multipurpose prevention technology (MPT) product to provide HIV pre-exposure prophylaxis (PrEP) and contraception to women in the developing world. MPT is a high priority for the NIH, the WHO and for leading NGOs. Our strategy is based on delivering the best-in-class HIV PrEP candidates using our proprietary and novel “intravaginal beads” in conjunction with FDA-approved contraceptive IVRs. Truvada® (TDF-FTC combination) is the only FDA-approved drug product for HIV PrEP. However, recent studies have shown NRTI-associated vaginal mitochondrial toxicity, including the data found in our Phase I SBIR efforts. In our original Phase II SBIR (Jan ’18) submission, we presented pre-clinical results for a TDF- FTC bead formulation, and a proposal to adapt the bead technology to the cabotegravir (CBT)-rilpivirine (RPV) combination. At that time, the FDA had just approved Juluca®, which till date remains to be the only two-drug (dolutegravir [DTG] + rilpivirine) medication for HIV treatment. In the past twelve months, several post- marketing studies of Juluca® have been published showing enhanced safety and efficacy. Additionally, the DTG-RPV combination can also act as PrEP agents at very low levels and has a long half-life with lesser known potential for mitochondrial toxicity than NRTIs. On the other hand, the CBT-RPV combination, although in late-stage clinical trials, is not yet approved by the regulatory agencies. Hence, given the significant regulatory and scientific advantages of DTG-RPV drug combination over CBT-RPV, we shifted our product development focus towards the former. One of the main concerns with our original submission was the lack of preliminary data. In response, we resubmit this application with pre-clinical results for the proposed drug selection. Briefly, a 1-month pharmacokinetics (PK) study was performed in a sheep model to evaluate feasibility of the DTG-RPV beads when delivered in combination with a contraceptive IVR (NuvaRing®). The beads demonstrated an average in vivo release of 2.4 mg/d DTG and 0.6 mg/d RPV. The resulting average cervicovaginal fluid (CVF) levels were 537 ng/ml DTG and 807 ng/ml RPV suggesting sustained delivery at concentrations greater than their respective EC50 levels. The drug loading capacity of these beads allows us to formulate them as 3-month beads making it feasible for use in combination with either a monthly Nuvaring® (in this scenario, one bead will be used for three consecutive monthly IVRs over a 3-month period) or a yearly Annovera® (here, four beads will be required for one IVR over a 12-month period), depending on the user’s choice. This Phase II SBIR resubmission proposes the following revised plan: In Year 1, we will manufacture pre- clinical batches of DTG and RPV beads; and conduct IND-enabling safety/PK studies in sheep and macaques. In Year 2, we will test the formulation for efficacy in a macaque model. Finally, we will perform IND-enabling chemistry, manufacturing and controls (CMC) activities for the lead formulation to submit an IND. We have been granted 13 IND approvals, and the only sustained release antiviral drug delivery device ever approved by the FDA (the Vitrasert®) was developed by the Principal Investigator of this proposal. Successful completion of the work described in this proposal will allow human testing of this novel intravaginal MPT.

摘要（更改以下划线表示） 这项研究计划的广泛，长期目标是开发一种阴道内多用途预防 艾滋病毒暴露前预防（PrEP）和避孕的妇女提供技术（MPT）产品， 发展中国家的团结合作MPT是NIH、WHO和主要非政府组织的高度优先事项。我们的战略基于 使用我们专有的新型“阴道内珠”提供一流的HIV PrEP候选药物， 与FDA批准的避孕IVRs结合使用。 Truvada®（TDF-FTC组合）是FDA批准的唯一用于HIV PrEP的药物产品。 研究表明NRTI相关的阴道线粒体毒性，包括我们在I期研究中发现的数据， SBIR的努力。在我们最初的II期SBIR（2018年1月）提交文件中，我们提供了TDF的临床前结果， FTC微珠制剂，以及将微珠技术适用于卡替拉韦（CBT）-利匹韦林（RPV）的建议 组合.当时，FDA刚刚批准了Juluca®，到目前为止，它仍然是唯一的两种药物 （dolutegravir [DTG] + rilpivirine）药物用于HIV治疗。在过去的12个月里，一些... 已发表的Juluca®的市场研究显示出增强的安全性和有效性。另夕h DTG-RPV组合也可以在非常低的水平下作为PrEP试剂，并且具有较长的半衰期， 已知潜在的线粒体毒性比NRTI。另一方面，CBT-RPV组合，虽然 在后期临床试验中，尚未得到监管机构的批准。因此，鉴于 DTG-RPV药物组合相对于CBT-RPV的监管和科学优势，我们将我们的产品 发展重点放在前者。 我们最初提交的主要关切之一是缺乏初步数据。作为回应，我们 重新提交本申请，并附上拟定药物选择的临床前结果。简而言之，一个月 在绵羊模型中进行药代动力学（PK）研究以评价DTG-RPV珠粒的可行性 当与避孕IVR（NuvaRing®）联合使用时。珠子显示出平均 DTG2.4mg/d和RPV 0.6mg/d的体内释放。平均宫颈阴道液（CVF）水平为 537 ng/ml DTG和807 ng/ml RPV表明浓度高于其可持续递送 EC 50水平。这些珠子的载药量使我们能够将其配制为3个月 珠粒使得其可与每月Nuvaring®（在这种情况下，一个珠粒将 在3个月的时间段内连续三个月使用IVRs）或每年使用Annovera®（此处，四个微珠 将需要在12个月内进行一次IVR），具体取决于用户的选择。 第二阶段SBIR重新提交提出了以下修订计划：在第一年，我们将生产预 DTG和RPV珠的临床批次;并在绵羊和猕猴中进行IND使能安全性/PK研究。 在第2年，我们将在猕猴模型中检测制剂的疗效。最后，我们将执行IND启用 用于提交IND的主要制剂的化学、生产和控制（CMC）活动。 我们已经获得了13个IND批准，并且是有史以来唯一的持续释放抗病毒药物递送装置。 由FDA批准（Vitrasert®）由本提案的主要研究者开发。成功 完成该建议中描述的工作将允许对这种新型阴道内MPT进行人体测试。